S148: VENETOCLAX-OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 5-YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY
Authors: O. Al-Sawaf, C. Zhang, S. Robrecht, A. Kotak, N. Chang, A.-M. Fink, E. Tausch, C. Schneider, M. Ritgen, K.-A. Kreuzer, B. Chyla, B. Eichhorst, Y. Jiang, S. Stilgenbauer, M. Hallek, K. Fischer
Journal: HemaSphere (2022)

Background: One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) has demonstrated significant improvement of progression-free survival (PFS) as compared to chlorambucil-obinutuzumab (Clb-Obi) in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting conditions in the CLL14 trial. As high rates of undetectable minimal residual disease (uMRD) suggested deep remissions, long-term efficacy data including patients with high-risk disease is of particular interest. Aims: The aim of this report is to provide updated efficacy and safety data from the ongoing follow-up of the CLL14 study with all patients being off study treatment for ≥ 4 years. Methods: Patients with previously untreated CLL and coexisting conditions were randomized 1:1 to 12 cycles of venetoclax with 6 cycles of obinutuzumab or 12 cycles of chlorambucil with 6 cycles of obinutuzumab. The primary endpoint was investigator-assessed PFS. Secondary endpoints included safety, rates of MRD response (measured every 3-6 months up to 9 years after last patient enrolment), time to next treatment (TTNT) and overall survival. Follow-up is ongoing, all patients are off study treatment. Results: Of the 432 enrolled patients, 216 were randomly assigned to receive Ven-Obi and 216 to receive Clb-Obi. With a current median follow-up of 65.4 months (interquartile range 52.6-69.4), PFS remained significantly superior for Ven-Obi compared to Clb-Obi (median not reached [nr] vs 36.4 months; hazard ratio [HR] 0.35 [95% CI 0.26-0.46], p<0.0001). At 5 years after randomization, the estimated PFS rate was 62.6% after Ven-Obi and 27.0% after Clb-Obi. Overall, 52 cases of progressive disease (PD) with 28 required second-line treatments occurred in the Ven-Obi arm and 132 with 86 second-line treatments in the Clb-Obi arm. TTNT was significantly longer after Ven-Obi (5-year TTNT 72.1% vs 42.8%; HR 0.42, 95% CI 0.31-0.57, p<0.0001). In both arms, the majority of next-line therapies were BTK inhibitors (54.3% in the Ven-Obi arm, 47.1% in the Clb-Obi arm). The PFS and TTNT difference was maintained across all risk groups, including patients with TP53 mutation/deletion (5-year PFS 40.6% vs 15.6%; 5-year TTNT 48.0% vs 20.8%) and unmutated IGHV status (5-year PFS 55.8% vs 12.5%; 5-year TTNT 66.2% vs 25.1%). A multivariable analysis indicated 17p deletion and high disease burden as independent prognostic factors for PFS in patients treated with Ven-Obi. Four years after treatment completion, 39 (18.1% of the intention-to-treat population) patients in the Ven-Obi arm still had uMRD (<10-4 by NGS in peripheral blood), 27 (12.5%) had low (L)-MRD (≥ 10-4 and < 10-2) and 41 (19.0%) high (H)-MRD (≥ 10-2), compared to 4 (1.9%) uMRD, 13 (6.0%) L-MRD and 24 (11.1%) H-MRD in the Clb-Obi arm. Overall, 40 deaths were reported in the Ven-Obi arm (8 PD related) and 57 in the Clb-Obi arm (23 PD related); at 5 years after randomization the estimated OS rate was 81.9% in the Ven-Obi arm and 77.0% in the Clb-Obi arm (HR 0.72 [0.48-1.09], p=0.12). Second primary malignancies were reported in 44 (20.8%) patients in the Ven-Obi arm and 32 (15.0%) in the Clb-Obi arm. No new safety signals were observed. Image:Summary/Conclusion: These data confirm that over 60% of patients who had received 1-year fixed-duration Ven-Obi have remained in remission four years after end of therapy. The majority of patients treated with Ven-Obi still have not required a second line of CLL therapy. Hence, the 1-year Ven-Obi regimen continues to be an effective fixed-duration option for patients with CLL and coexisting conditions, also in the context of high-risk disease.